Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors.

Epigenetic and genomic alterations regulate the transcriptional landscape of cells during cancer onset and progression. Recent clinical studies targeting the epigenetic 'readers' (bromodomains) for cancer therapy have established the effectiveness of bromodomain (BRD) and extraterminal (BET) inhibitors in treating several types of cancer. In this review, we discuss key mechanisms of BET inhibition and synergistic combinations of BET inhibitors with histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), kinase, B-cell lymphoma 2 (Bcl-2) and proteosome inhibitors, and immunomodulatory drugs for cancer therapy. We also highlight the potential of such combinations to overcome drug resistance, and the evolving approaches to developing novel BET inhibitors.